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Alteracions Epigenètiques En Càncer Colorectal: Canvis Globals I

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Alteracions Epigenètiques En Càncer Colorectal: Canvis Globals I Alteracions epigenètiques en càncer colorectal: canvis globals i identificació de noves dianes Memòria presentada per Jairo Rodríguez Lumbiarres per optar al grau de Doctor en Biologia Tesi realitzada sota la direcció del Dr. Miquel Àngel Peinado a l‟IDIBELL-Institut de Recerca Oncològica. Tesi adscrita al Departament de Genètica de la Facultat de Biologia Universitat de Barcelona. Programa de Genètica, bienni 2003-2005. Director Tutor Miquel À. Peinado Ricard Albalat Jairo Rodríguez Barcelona, Novembre de 2007 OBJECTIUS Objectius 51 Objectius 1. Determinar la relació entre canvis globals de la metilació genòmica amb alteracions genètiques en tumors primaris humans. 2. Identificació de noves regions hipometilades en tumors colorectals amb una especial atenció sobre aquelles que continguin elements repetitius Alu. En aquest objectiu s‟hi inclou tant el mapatge com la quantificació d‟elements Alu desmetilats en cèl·lules normals i tumorals. 3. Identificació de noves regions hipermetilades en tumors colorectals i caracterització dels canvis epigenètics associats al silenciament. RESULTATS Resultats 55 CAPÍTOL 1 Chromosomal instability correlates with genome-wide DNA demethylation in human primary colorectal cancers Jairo Rodríguez, Jordi Frigola, Elisenda Vendrell, Rosa-Ana Risques, Mario F. Fraga, Cristina Morales, Víctor Moreno, Manel Esteller, Gabriel Capellà, Miguel A. Peinado. Cancer Research, 2006, Vol.66 (17): 8462-8468. Els dos primers autors han contribuït per igual en aquest treball. Resultats 56 Chromosomal instability correlates with genome-wide DNA demethylation in human primary colorectal cancers Aquest treball descriptiu es centra bàsicament en l‟anàlisi de la relació existent entre alteracions genètiques i epigenètiques en tumors de CCR humans. Si bé les evidències assenyalaven que podia existir una relació causal entre hipometilació i inestabilitat genètica en diferents models, aquesta relació no s‟havia pogut veure de forma clara en tumors primaris humans. Un únic treball previ publicat l‟any 2005 indica que existeix en tumors primaris humans de CCR una correlació positiva entre nivells d‟hipometilació mesurats en elements repetitius LINE i pèrdua d‟heterozigositat en determinats loci. Tot i aquests resultats, limitacions tècniques en la mesura del grau de hipometilació (els autors mesuren el nivell d‟hipometilació amb una única determinació per PCR) així com la determinació d‟alteracions cromosòmiques en un nombre reduït de loci limiten el impacte dels resultats obtinguts. En aquest treball, es presenten de forma conjunta els resultats obtinguts per Jordi Frigola sobre una sèrie de 83 tumors colorectals i per mi mateix sobre una segona sèrie de 50 tumors colorectals. En la primera sèrie, l‟anàlisi del grau de metilació de les mostres es realitza per AIMS. Sobre la mateixa sèrie de mostres es va calcular dany genètic per mitjà de AP-PCR. Aquesta tècnica de fingerprinting de DNA permet avaluar de forma ràpida i senzilla alteracions genètiques al llarg de tot el genoma amb la particularitat que no podem distingir entre mutacions puntuals, pèrdues o guanys de material genètic (fragments o cromosomes sencers) i reorganitzacions cromosòmiques. Els resultats obtinguts en aquesta primera sèrie indiquen que existeix una correlació positiva entre els nivells d‟hipometilació de les mostres i el nombre d‟alteracions genètiques observades per AP-PCR. En la segona sèrie, si bé l‟anàlisi del grau d‟hipometilació dels tumors va ser idèntic per mitjà de AIMS, la quantificació d‟alteracions genètiques va ser duta a terme per mitjà de la tècnica de Comparative Genomic Hibridization o CGH. Aquesta tècnica permet veure alteracions cromosòmiques relativament grans de tipus numèric, com poden ser els guanys i pèrdues de fragments cromosòmics o cromosomes sencers, així com delecions o amplificacions de fragments cromosòmics relativament grans. En aquest cas però, no podem veure alteracions estructurals balancejades, es a dir, aquelles que no impliquen guanys o pèrdues netes de material genètic. En aquest cas també vàrem observar una correlació positiva entre el grau de hipometilació en tumor i el nombre d‟alteracions cromosòmiques, si bé la correlació era molt més bona que la observada en la primera sèrie de mostres. Aquest fet és indicatiu que el tipus d‟inestabilitat associada a desmetilació és bàsicament de tipus cromosòmic, donat que quan mesurem les alteracions genètiques d‟origen exclusivament cromosòmic la correlació observada amb el grau d‟hipometilació és significativament millor que la obtinguda entre hipometilació i alteracions genètiques de divers origen mesurades per AP-PCR. La disposició de dades clínico- patològiques de la sèrie de 50 tumors colorectals va permetre establir que la correlació entre hipometilació i alteracions cromosòmiques és independent de mutacions en altres gens importants per al manteniment de la integritat del genoma com p53, fet que indica, però no demostra, que la hipometilació pot ser causa del dany cromosòmic en tumors primaris humans. Resultats 57 Resultats 58 Resultats 59 Resultats 60 Resultats 61 Resultats 62 Resultats 63 Resultats 64 Supplemental Material PATIENTS Two series of patients preoperatively diagnosed of colorectal cancer and operated upon with curative or palliative intention were used in this study. HSP series consisted of 83 patients from the Hospital de Sant Pau (Barcelona, Spain). HUB series consisted of 50 patients from the Ciutat Sanitària i Universitària de Bellvitge (L‟Hospitalet, Barcelona, Spain). Patients were prospectively included in a study specifically designed to evaluate the prognostic value of genetic alterations in colorectal cancer and to evaluate the relationships between diet and molecular alterations. No chemo- or radiotherapy was given prior to surgery in these patients. Inclusion in the study did not influence the adjuvant treatment given. The study protocol was approved by the Ethics Committee. Inclusion criteria in both series were: (a) electively resected primary adenocarcinomas; (b) the obtention of fresh paired normal mucosa-tumor samples within two hours after tumor removal; (c) availability of high quality DNA from paired normal and tumor tissue; and (d) no postoperative death. Additionally, HUB series only included Dukes B and C stage tumors and series HSP only included tumors negative for microsatellite instability (83 from an original collection of 93 cases) to avoid the detection of microsatellite related instability in the determination of genomic damage by Arbitrarily Primed PCR (AP-PCR) fingerprints. In series HUB it was not necessary to exclude tumors with microsatellite instabity (n=3) because it is not detected by Comparative Genomic Hybridization. Cases were pathologically staged using Astler-Coller modification of Dukes' classification system. Surgical specimens were collected at the operating room and immediately taken to the Pathology Department in ice. Carcinomas and paired normal samples were snap frozen within two hours after removal and then stored at -80ºC. Localization stage Dukes’ Sex Age tumorsAll Female Right > 67> 67≤ Male Left C A - - D B 63 20 39 44 46 37 47 36 83 n p=0.102 p=0.494 p=0.814 p=0.744 0.181 0.181 ± 0.145 ± 0.165 ± 0.178 ± 0.168 ± 0.175 ± 0.175 ± 0.169 ± 0.172 ± 0.086 0.076 0.081 0.088 0.077 0.092 0.086 0.084 0.085 GDF Series Series HSP Hypomethylation 0.152 0.0890.152 ± 0.0560.139 ± 0.0850.139 ± 0.0790.157 ± 0.0770.168 ± 0.0830.125 ± 0.0800.138 ± 0.0840.162 ± 0.0820.149 ± p=0.016 p=0.554 p=0.336 p=0.200 Index 65 Supplemental Table 1. Indices of Genomic Damage and DNA hypomethylation in colorectal carcinomas classified by clinicopathological featuresa. Resultats 35 15 21 29 26 24 22 28 50 n Alterations 7.5 5.57.5 ± 4.66.5 ± 4.37.4 ± 5.26.4 ± 5.07.6 ± 4.56.0 ± 4.38.1 ± 5.05.8 ± 6.8 ± p=0.512 p=0.506 p=0.241 p=0.455 No of 4.8 Series Series HUB Hypomethylation 0.120 0.0640.120 ± 0.0570.125 ± 0.0630.122 ± 0.0620.122 ± 0.0610.122 ± 0.0640.122 ± 0.0600.129 ± 0.0630.116 ± 0.0620.122 ± p=0.788 p=0.999 p=0.978 p=0.093 Index Resultats 66 Supplemental Table 2. Correlation between genomic damage and the hypomethylation index in colorectal cancers classified according to clinicopathological features Series HSP Series HUB Variable n Correlationa p n Correlationa p All tumors 83 0.250 0.022 50 0.514 <0.001 Age ≤ 67 36 0.519 0.001 23 0.530 0.009 > 67 47 0.057 0.715 27 0.538 0.004 Sex Female 37 0.241 0.151 24 0.342 0.102 Male 46 0.293 0.048 26 0.681 <0.001 Dukes’ stage A-B 44 0.185 0.228 29 0.443 0.016 C-D 39 0.313 0.052 21 0.647 0.002 Localization Right 20 0.399 0.081 15 0.288 0.297 Left 63 0.218 0.086 35 0.618 <0.001 p53 status wild type 46 0.263 0.077 17 0.644 0.005 mutated 33 0.177 0.323 33 0.425 0.014 a Pearson‟s correlation. Supplemental Table 3. Correlationa among the Hypomethylation index and the number of different types of chromosmal alterations Losses Gains Numerical Estructural Hypomethylation index 0.530 0.427 0.3610 0.510 <0.001 0.002 0.010 <0.001 Losses 0.748 0.743 0.845 <0.001 <0.001 <0.001 Gains 0.886 0.726 <0.001 <0.001 Numerical 0.489 <0.001 a Pearson‟s coefficient (p value is shown bold) (n=50). Resultats 67 CAPÍTOL 2 Genome-wide tracking of unmethylated DNA Alu repeats in normal and cancer cells Jairo Rodríguez, Laura Vives, Mireia Jordà, Cristina Morales, Mar Muñoz, Elisenda Vendrell, Miguel A. Peinado Article enviat a la revista Nucleic Acids Research. Resultats 68 Genome-wide tracking of unmethylated DNA Alu repeats in normal and cancer cells Durant dècades els elements repetitius de DNA, considerats els paràsits més senzills, han fascinat als investigadors, els quals han intentat desxifrar quin pot ser el paper d‟aquests elements en altres temps considerats DNA “escombraries” (junk DNA).
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